The tetradecapeptide somatostatin was characterized by Guillemin et al. and is described in U.S. Pat. No. 3,904,594 (Sept. 9, 1975.) The tetradecapeptide has the formula: ##STR2## wherein there is a bridging bond between the sulfhydryl groups of the two cysteinyl amino acid residues. The tetradecapeptide in its linear form (sometimes referred to as dihydrosomatostatin), wherein this bridging bond is not present and is replaced by hydrogen, is for purposes of this application considered to be included in the definition "somatostatin" as it appears to have substantially the same biological activity.
Somatostatin and many analogs of somatostatin exhibit activity in respect to the inhibition of growth hormone (GH) secretion from cultured, dispersed rat anterior pituitary cells in vitro and also in vivo and with respect to the inhibition of insulin and glucagon secretion in vivo in the rat and in other mammals. Somatostatin has also been found to inhibit the secretion of gastrin and secretin by acting directly upon the secretory elements of the stomach and pancreas respectively. In addition to being found in the hypothalamus, somatostatin also occurs in neuronal elements and axonal fibers in multiple locations in the central nervous system, including the spinal cord, and in discrete secretory cells of classical epithelial layers in all the parts of the stomach, gut, and pancreas, in which it was first recognized as having an inhibitory effect. The powerful inhibitory effects of somatostatin on the secretion not only of GH but also of insulin and glucagon have led to studies of a possible role of somatostatin in the management or treatment of juvenile diabetes and have proved useful in studying the physiological and pathological effects of these hormones on human metabolism. Such studies, showing that somatostatin lowers plasma glucose concentrations in normal man despite its inhibitory effect on insulin, have provided the first clear-cut evidence that glucagon has an important physiological role in human carbohydrate homeostasis.
In juvenile-type diabetics, somatostatin diminishes fasting hyperglycemia by as much as 50 percent in the complete absence of circulating insulin. Somatostatin impairs carbohydrate tolerance in normal humans given oral or intravenous glucose by inhibiting insulin secretion; however, carbohydrate tolerance after ingestion of balanced meals is improved in patients with insulin-dependent diabetes mellitus through the supression of excessive glucagon responses. The combination of somatostatin and a suboptimal amount of exogenous insulin (which by itself prevents neither excessive hyperglycemia nor hyperglucagonemia in response to meals) completely prevents plasma glucose concentrations from rising after meal ingestion in insulin-dependent diabetics. Through its suppression of glucagon and GH secretion, somatostatin has also been shown to moderate or prevent completely the development of diabetic ketoacidosis after the acute withdrawal of insulin from patients with insulin-dependent diabetes mellitus.
In view of its ability to inhibit the secretion of such hormones, somatostatin may be therapeutically employed in clinical conditions for the treatment of acromegaly, pancreatic islet cell tumors and diabetes mellitus. Because somatostatin has a relatively short duration of action, apparently because it is inactivated by peptidases when administered in vivo, the search has continued for longer-acting somatostatin materials, as well as for somatostatin analogs which are more potent than somatostatin or which are both more potent and exhibit dissociated inhibitory functions.